This confederation of projects is headed by Mark I. Greene who has been involved in the study of immune regulation and phenotype reversal for over 30 years. The goals of this highly integrated program project are to develop understanding of how the FoxpS proteins exert their biological effects and through this knowledge to develop translationally relevant therapeutics that disable or activate the Foxp3 complex. Although the theme of Foxp3 function resonates in each project, a variety of distinct technologies are actually employed to develop insights into how Foxp3 complexes operate and how to manipulate them, leading to a highly interactive group of experiments that should lead to therapeutics that will reach the clinic within the time frame of this program project. The long-term goals are reiterated in every project and all projects share recurrent themes of Treg phenotype manipulation. The studies to date have already lead to a rational therapeutic for autoimmune conditions that is entering a preliminary clinical trial at the NIH. The goal of Greene's project is to provide basic biochemical information of how the Foxp3 complex binds to chromatin in human cells. This information will be helpful in Andrew Wells's study of mouse chromatin - Foxp3 interactions and will be useful in the creation of transgenic and mutant mice that will help the Hancock project and the Wells project. Human and mouse Foxp3 complexes appear to have differences although both form large ensembles. The intent of Project 1 is to identify individual residues that are acetylated and phosphorylated and subdomains that mediate interactions with other repressive components. This information will provide a framework for Andrew Wells to examine chromatin remodeling events in the mouse and for Wayne Hancock to examine functional relevance in in vivo models.